Could Orca-T Unlock New Path of Reduced Mortality, Prevent GVHD Posttransplant?

Steven Devine, MD

Orca-T is a novel approach to precision medicine in oncology, according to Steven Devine, MD, adding that longer follow-up and prospective, randomized studies will unlock the true potential of this technology as a means to improve survival and prevent graft-versus-host disease (GVHD) in patients with hematologic cancers. 

Early findings of a multicenter experience, which were presented during the 2020 ASH Annual Meeting, demonstrated that Orca-T prevented GVHD with less immunosuppression compared with a contemporaneous cohort of patients with high-risk hematologic malignancies who underwent standard-of-care hematopoietic stem cell transplantation. 

Data also showed that the rate of treatment-related mortality was reduced to 0% with Orca-T compared with 11% with the contemporaneous control arm (P = .04). The GVHD and relapse-free survival rate (GRFS) was 75% with Orca-T vs 31% with standard of care (P = .001).

“This approach is different because you try to precisely define the constituents of the graft that have benefit, removing those that may potentially cause problems, such as GVHD,” said Devine, associate scientific director of the Center for International Blood and Marrow Transplant Research. “Therefore, it is sort of a newer precision medicine approach to transplantation. It is more difficult, but the exciting aspect here is it looks like it is feasible. We'll just need to sit back and see as this expands to more centers.”

Devine is also chief medical officer of the National Marrow Donor Program/Be The Match, and co-scientific director of the Resource for Clinical Investigation in Blood and Marrow Transplant. Furthermore, he has background as a hematologist-oncologist and a foundation in blood and marrow transplant since the early 1990s. Not only was he director of the Blood Marrow Transplant Program at Ohio State University, but he has been heavily involved with the Blood and Marrow Transplant Clinical Trials Network.

In an interview with OncLive^®, Devine discussed the non-relapse mortality data with Orca-T and how this technologic approach is changing how providers approach patients with hematologic malignancies following transplant.

OncLive®: Data were recently presented on Orca-T at the 2020 ASH Annual Meeting. Could you discuss the survival benefit that we saw with this precision Treg-engineered donor product?

Devine: There are 2 primary ways to prevent GVHD after a transplant. The most common way is to use pharmacological agents, like cyclosporine and other drugs, because it's much easier. 

The other broad category is graft manipulation; we actually do something to the graft to try to remove the T cells that might cause GVHD. Fewer programs use that method because it's much more complicated. 

Therefore, the Orca-T study is using a more complicated, but centralized approach to actually defining the optimal constituents of a graft that might lead to greater graft-versus-leukemia effects, and a greater ability to prevent infection without GVHD. That is the overriding goal. This study is just looking at the safety of that and preliminary efficacy.

The data that were reported at the 2020 ASH Annual Meeting was in 50 patients, and mostly came out of initial work from Stanford University. The product was developed at Stanford University and has been licensed by Orca Bio. What they did is compare the clinical outcomes in the 50 trial participants to a historical control group—it was a little more than 140 patients—that had been treated similarly at Stanford University. 

They found that engraftment of both neutrophils and platelets was faster with Orca-T, and there was much lower non-relapse mortality [rate], which means dying of a complication of transplant, and less [cases of] both moderate and severe, acute and chronic GVHD, which leads to better overall survival. 

The caveats are that it wasn't a prospective, randomized comparison. It was retrospective, and as you know, patients on clinical trials tend to be more selected. While it's very, very encouraging, it's not definitive—but it does suggest clinical benefit.

Where do you think that these types of technologies are going to lead? Could this be the way to unlocking the 7/8 match?

That is certainly something the National Marrow Donor Program is interested in. How do we improve outcomes, not only for the patients who have well-matched donors, but what about all of the people who don't necessarily have access to a well-matched donor? That would include ethnic minorities; we have a much more difficult time finding fully matched donors, for instance, for African American patients who could benefit from transplant.

One of the things that we really want to learn more about is how this works in patients who have 1 antigen or allele mismatch. It could be really exciting if you could see less GVHD and less graft failure, but still retain the graft versus malignancy effect. That's something we are all very excited to hear more about.

What really excites you the most about these data?

One of the concerns with T-cell depletion, particularly when you remove almost all of the T cells, is that there could be a higher risk of relapse. Remember, these patients have hematological malignancies, so they're being treated to prevent their leukemia or lymphoma from relapse. The absence of significant toxicity, particularly non-relapse mortality, the absence of graft failure, yet the retention of what appears to be a graph versus malignancy effect, I think were the most interesting aspects of the trial. 

Of course, there needs to be a lot more follow-up. An additional caveat is that the follow-up is short. The data are very encouraging and certainly tell us that we need to treat more patients with this approach to really learn more about the effectiveness.

What are some of the differences in the infrastructure with centralized manufacturing? What is the accessibility to transplanters across the country?

That's really the big question. This is something that can be exported to a large number of centers, especially when you have to transport the cells from where they're collected, then to a manufacturing site, then back to the transplant centers. Therefore, I think the logistics are one of the more challenging aspects.

What we learned is that, in the patients who have been treated on this trial, there didn't seem to be any manufacturing problems or manufacturing failures. The grafts were able to be vein-to-vein delivered from where they were collected to the manufacturing site, and then back to the transplant centers within 72 hours, which shouldn't have any substantial effect on the viability or function of the cell. Initially, the ability to do this set of central manufacturing sites seems to be feasible, and that's very encouraging.

Finally, how do you think that these data will eventually help give sites access to Orca-T? What is the importance of the timeliness of deliberately?

Success breeds success. The study, which was initially developed at a single center, Stanford University, is now being tested at about 4 or 5 centers. Early studies typically involve smaller number centers, but the real test will be: How about if we expand this out to 10 or 20 centers? Is that feasible? Can we still keep those manufacturing timelines and delivery times short? That will be the test, because patients are then less selected when you look at them at a variety of centers that use different criteria for how [providers] choose their patients for transplant. It shows that this would be feasible to break it out into a larger study. It will be interesting to see, when that happens, if the results look similar to these very encouraging preliminary data.

Reference

1. Meyer EH, Hoeg R, Moroz A, et al. Orca-T, a precision Treg-engineered donor product, prevents acute GvHD with less immunosuppression in an early multicenter experience with myeloablative HLA-matched transplants. Orca Bio. December 6, 2020. Accessed December 6, 2020. https://bit.ly/39URbD4.